Infection caused by multidrug-resistant Gram-negative bacteria has become a major threat to public health. Over the last 40 years, no truly novel class of antibiotics against Gram-negative bacteria has been introduced to the market. This, coupled with emergence of antibiotic resistance highlights the urgent need for new antibiotics. Cationic peptides represent a huge family of antibiotics and have attracted extensive interest with their diverse chemical structures and great potential for combating Gram-negative pathogens. Cationic nonribosomal peptides, including polymyxins and gramicidin S, are the most structurally diverse families of cationic peptides with great antimicrobial potential.
Cationic peptides are found in all forms of life (mammals, plants, and bacteria), and are among the most widespread and structurally-diverse antibiotics in nature. Carrying unique chemical properties that not only facilitate their penetration through the highly impermeable outer membrane of Gram-negative bacteria but also enable their interaction with multiple anionic intracellular targets, cationic peptides are highly effective against drug-resistant Gram-negative pathogens. In the past four decades, thousands of cationic peptides with broad antimicrobial activities have been identified and most of them are natural or naturally derived host defense peptides from multicellular organisms. However, only a handful of these cationic peptides have entered clinical application, due to their high cost of supply, instability to proteolytic degradation, and unknown toxicological profile. Bacterial cationic nonribosomal peptides (CNRPs) with sufficient supply and proteolytic stability are attractive therapeutic candidates. Polymyxins and gramicidin S produced by bacilli bacteria are among the few precedents with clinical efficacy. However, the diversity and complexity of CNRPs have made systematic investigation difficult and consequently, the vast majority of genetically encoded CNRPs in bacteria have been overlooked and remain unknown.